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BackgroundPediatric tuberculous meningitis (TBM) commonly causes death or disability. In adults, high-dose rifampicin may reduce mortality. The role of fluoroquinolones remains unclear. There have been no antimicrobial treatment trials for pediatric TBM.MethodsTBM-KIDS was a phase 2 open-label randomized trial among children with TBM in India and Malawi. Participants received isoniazid and pyrazinamide plus: (i) high-dose rifampicin (30 mg/kg) and ethambutol (R30HZE, arm 1); (ii) high-dose rifampicin and levofloxacin (R30HZL, arm 2); or (iii) standard-dose rifampicin and ethambutol (R15HZE, arm 3) for 8 weeks, followed by 10 months of standard treatment. Functional and neurocognitive outcomes were measured longitudinally using Modified Rankin Scale (MRS) and Mullen Scales of Early Learning (MSEL).ResultsOf 2487 children prescreened, 79 were screened and 37 enrolled. Median age was 72 months; 49%, 43%, and 8% had stage I, II, and III disease, respectively. Grade 3 or higher adverse events occurred in 58%, 55%, and 36% of children in arms 1, 2, and 3, with 1 death (arm 1) and 6 early treatment discontinuations (4 in arm 1, 1 each in arms 2 and 3). By week 8, all children recovered to MRS score of 0 or 1. Average MSEL scores were significantly better in arm 1 than arm 3 in fine motor, receptive language, and expressive language domains (P

IntroductionHost lipids play important roles in tuberculosis (TB) pathogenesis. Whether host lipids at TB treatment initiation (baseline) affect subsequent treatment outcomes has not been well characterised. We used unbiased lipidomics to study the prospective association of host lipids with TB treatment failure.MethodsA case-control study (n=192), nested within a prospective cohort study, was used to investigate the association of baseline plasma lipids with TB treatment failure among adults with pulmonary TB. Cases (n=46) were defined as TB treatment failure, while controls (n=146) were those without failure. Complex lipids and inflammatory lipid mediators were measured using liquid chromatography mass spectrometry techniques. Adjusted least-square regression was used to assess differences in groups. In addition, machine learning identified lipids with highest area under the curve (AUC) to classify cases and controls.ResultsBaseline levels of 32 lipids differed between controls and those with treatment failure after false discovery rate adjustment. Treatment failure was associated with lower baseline levels of cholesteryl esters and oxylipin, and higher baseline levels of ceramides and triglycerides compared to controls. Two cholesteryl ester lipids combined in a unique classifier model provided an AUC of 0.79 (95% CI 0.65-0.93) in the test dataset for prediction of TB treatment failure.ConclusionsWe identified lipids, some with known roles in TB pathogenesis, associated with TB treatment failure. In addition, a lipid signature with prognostic accuracy for TB treatment failure was identified. These lipids could be potential targets for risk-stratification, adjunct therapy and treatment monitoring.

The female genital tract (FGT) is an important site of human immunodeficiency virus (HIV) infection. Discerning the nature of HIV-specific local immune responses is crucial for identifying correlates of protection in HIV-exposed seronegative (HESN) individuals. The present study involved a comprehensive analysis of soluble immune mediators, secretory immunoglobulins (sIg), natural killer (NK) cells, CXCR5+ CD8+ T cells, T follicular helper (Tfh) cells, and T regulatory cells (Tregs) in the vaginal mucosa as well as the nature and composition of the cervicovaginal microbiome in HESN women. We found significantly elevated antiviral cytokines, soluble immunoglobulins, and increased frequencies of activated NK cells, CXCR5+ CD8+ T cells, and Tfh cells in HESN females compared to HIV-unexposed healthy (UH) women. Analysis of the genital microbiome of HESN women revealed a greater bacterial diversity and increased abundance of Gardnerella spp. in the mucosa. The findings suggest that the female genital tract of HESN females represents a microenvironment equipped with innate immune factors, antiviral mediators, and critical T cell subsets that protect against HIV infection. IMPORTANCE The vast majority of human immunodeficiency virus (HIV) infections across the world occur via the sexual route. The genital tract mucosa is thus the primary site of HIV replication, and discerning the nature of HIV-specific immune responses in this compartment is crucial. The role of the innate immune system at the mucosal level in exposed seronegative individuals and other HIV controllers remains largely unexplored. This understanding can provide valuable insights to improve vaccine design. We investigated mucosal T follicular helper (Tfh) cells, CXCR5+ CD8+ T cells, natural killer (NK) cells subsets, soluble immune markers, and microbiome diversity in HIV-exposed seronegative (HESN) women. We found a significantly higher level of mucosal CXCR5+ CD8+ T cells, CD4+ Tfh cells, activated NK cell subsets, and antiviral immune cell mediators in HESN women. We also found a higher abundance of Gardnerella spp., microbiome dysbiosis, and decreased levels of inflammatory markers to be associated with reduced susceptibility to HIV infection. Our findings indicate that increased distribution of mucosal NK cells, CXCR5+ CD8+ T cells, Tfh cells, and soluble markers in HIV controllers with a highly diverse cervicovaginal microbiome could contribute effectively to protection against HIV infection. Overall, our findings imply that future vaccine design should emphasize inducing these highly functional cell types at the mucosal sites.

Broadly Cross clade Neutralizing (BCN) antibodies are recognized as potential therapeutic tools and leads for the design of a vaccine that can protect human beings against various clades of Human Immunodeficiency Virus (HIV). In the present study, we screened plasma of 88 HIV-1 infected ART naïve individuals for their neutralization potential using a standard panel of 18 pseudoviruses belonging to different subtypes and different levels of neutralization. We identified 12 samples with good breadth of neutralization (neutralized >90% of the viruses). Four of these samples neutralized even the difficult-to-neutralize tier-3 pseudoviruses with great potency (GMT > 600). Analysis of neutralization specificities indicated that four samples had antibodies with multiple epitope binding specificities, viz. CD4-binding site (CD4BS), glycans in the V1/V2 and V3 regions and membrane proximal external region (MPER). Our findings indicate the strong possibility of identifying highly potent bNAbs with known or novel specificities from HIV-1 subtype C infected individuals from India that can be exploited as therapeutic tools or lead molecules for the identification of potential epitopes for design of a protective HIV-1 vaccine.

Revolutionary progress in combinational antiretroviral therapy has transformed human immunodeficiency virus (HIV) infection into a chronic manageable disease; yet, there exists an uneasy truce between the virus and the immune cells, where inflammation is limited but infection continues to fester from latent reservoirs of the virus. Clinical studies have identified the major immune cell types that constitute the latent HIV-1 reservoirs as monocytes/macrophages and CD4+ T cells. Latency probing approaches have thrown some light on the interaction between the virus and the reservoir cells from the time of onset of infection. However, research combining latency reversal strategies and immunotherapies face daunting obstacles in clinical trials because of the lack of in-depth knowledge on viral pathogenesis and mechanisms of viral evasion, leaving us behind in the battle for HIV cure. This article reviews existing knowledge on the cells and mechanisms that contribute to the establishment and survival of HIV reservoirs in infected individuals. [ABSTRACT FROM AUTHOR]

Background The positive predictive value of tuberculin skin test and current generation interferon gamma release assays are very low leading to high numbers needed to treat. Therefore, it is critical to identify new biomarkers with high predictive accuracy to identify individuals bearing high risk of progression to active tuberculosis (TB). Methods We used stored QuantiFERON supernatants from 14 household contacts of index TB patients who developed incident active TB during a 2-year follow-up and 20 age and sex-matched non-progressors. The supernatants were tested for an expanded panel of 45 cytokines, chemokines, and growth factors using the Luminex Multiplex Array kit. Results We found significant differences in the levels of TB-antigen induced production of several analytes between progressors and non-progressors. Dominance analysis identified 15 key predictive biomarkers based on relative percentage importance. Principal component analysis revealed that these biomarkers could robustly distinguish between the 2 groups. Receiver operating characteristic analysis identified interferon-γ inducible protein (IP)-10, chemokine ligand (CCL)19, interferon (IFN)-γ, interleukin (IL)-1ra, CCL3, and granulocyte-macrophage colony-stimulating factor (GM-CSF) as the most promising predictive markers, with area under the curve (AUC) ≥90. IP-10/CCL19 ratio exhibited maximum sensitivity and specificity (100%) for predicting progression. Through Classification and Regression Tree analysis, a cutoff of 0.24 for IP-10/CCL19 ratio was found to be ideal for predicting short-term risk of progression to TB disease with a positive predictive value of 100 (95% confidence interval [CI] 85.8–100). Conclusions The biomarkers identified in this study will pave way for the development of a more accurate test that can identify individuals at high risk for immediate progression to TB disease for targeted intervention. [ABSTRACT FROM AUTHOR]